Abstract 5673: Characterization of AB598, a therapeutic anti-human CD39 antibody for the treatment of cancer
Authors: Amy E. Anderson, Angelo Kaplan, Urvi Vani, Enzo Stagnaro, Kaustubh Parashar, Julie Clor, Nigel P. Walker, Steve W. Young, Matthew J. Walters, Ester Fernandez-Salas, Christine E. Bowman, Lisa Seitz
Journal: Cancer Research (2023)

Abstract Background: CD39 catalyzes the conversion of extracellular adenosine triphosphate (ATP) into adenosine monophosphate (AMP), resulting in decreased levels of immunostimulatory ATP and increased levels of immunosuppressive adenosine in the tumor microenvironment (TME). By blocking CD39 in the TME, particularly in combination with immunogenic cell death (ICD)-inducing chemotherapies, local levels of ATP can increase, leading to myeloid cell activation and improved tumor control. AB598 potently binds and inhibits enzymatic activity of human and cynomolgus CD39 but not murine CD39. Human CD39 knock-in (hCD39KI) mice have been employed to determine anti-tumor efficacy of AB598 in animals with competent immune systems. Methods: Binding affinity and enzymatic inhibition of AB598 were determined in primary human immune cells. ATP-mediated activation of monocyte-derived dendritic cells (moDCs) and macrophages were assayed in vitro with and without AB598. Whole blood and tissue-based receptor occupancy (RO) assays were developed using AB598-competitive and non-competitive anti-CD39 reagents. In vitro binding of AB598 was determined in samples from human and cynomolgus donors. CD39 protein expression, target engagement, and enzymatic inhibition were assessed in whole blood and tissue samples collected from AB598-dosed animals. CD39 expression patterns in peripheral immune subsets were confirmed in samples from healthy human donors. CD39 enzymatic activity was evaluated in blood-derived cells and serum from healthy human donors and cancer patients. Results: AB598 binds to CD39-expressing monocytes, B cells, and other immune cell populations in human and cynomolgus whole blood with sub-nanomolar affinity. Following AB598 dosing in preclinical species, decreases in CD39 surface expression on peripheral immune cells were observed, consistent with other anti-CD39 therapeutic antibodies. Target engagement and enzymatic inhibition were evident in tissues collected from AB598-dosed animals. Treatment with AB598/chemotherapy combinations resulted in significant syngeneic tumor control in hCD39KI mouse models. Conclusion: When used in combination with an ICD-inducing chemotherapy agent, AB598 can promote anti-tumor immunity by activation of myeloid cells due to increased local ATP levels. Preclinical characterization of the pharmacodynamic effects of AB598 support our therapeutic rationale and demonstrate target engagement and inhibition both peripherally and intratumorally. Citation Format: Amy E. Anderson, Angelo Kaplan, Urvi Vani, Enzo Stagnaro, Kaustubh Parashar, Julie Clor, Nigel P. Walker, Steve W. Young, Matthew J. Walters, Ester Fernandez-Salas, Christine E. Bowman, Lisa Seitz. Characterization of AB598, a therapeutic anti-human CD39 antibody for the treatment of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5673.